How do brain changes, inflammation, and genetic risk factors modulate the development of PTSD or depression in patients with a history of trauma?
Charles Nemeroff, MD, PhD
PSYCHED! A PSYCHIATRY PODCAST
with David Carreon, MD and Jessica A. Gold, MD, MS
Charles Nemeroff, MD, PhD, discusses the role of social influences on biology, using the example of early life trauma. He explains brain changes, inflammation, and genetic risk factors that modulate the development of PTSD or depression in patients with a history of trauma.
Keeping in line with epigenetic theory, Dr. Nemeroff discusses what happens to genes during psychotherapy, exploring the interaction between attachment to the therapist and how this contributes to the efficacy.
Finally, he answers our rapid-fire questions and describes the challenges without parity in mental health care. He leaves us with excitement and hope for what he feels is the “golden age of psychiatry.”
Part 1: Depression: A Killing Disease
David Carreon: I think that on the positive end, I think there's more research to do, but I think thinking about this relationship between the mind and the body, and the person's experience ... It makes me think of things like a difficult childhood, child abuse, or something like that could very well increase a person's stress level and inflammatory markers.
Dr. Nemeroff: Well, you're prescient, because that's exactly what the data show. There's a wonderful meta-analysis by Andrea Danese at the Institute of Psychiatry in London. We've confirmed the findings in our own studies. Early life trauma is associated with a very persistent increase in inflammatory markers, and it's probably one of the reasons why those patients have a poorer response to psychotherapy and pharmacotherapy.
Jessi Gold: And what counts as early life, and is it one trauma, multiple traumas, or is it different?
Dr. Nemeroff: So another great question. The data is still being generated, but overall pre-pubertal abuse and neglect. The more severe, the worse the outcome, both in terms of inflammation, but also a host of other factors. Neuroanatomical changes ... The human brain doesn't mature until age 24, and we know that developing protoplasm is susceptible to insult. Susceptible to lead toxicity, susceptible to fetal alcohol, and in my way of thinking, it's susceptible to behavioral teratology, namely child abuse and neglect. So it's not surprising that we've seen these robust effects that we have.
David Carreon: Yeah, and I think there's been an interesting body of literature developing around the social influences on biology. Rats that are isolated versus rats that are in paired housing versus rats that are in enriched environments have entirely different profiles of how they do and how they behave, and what that means for them. And I guess thinking about that both in childhood, but throughout the life, that environment plays a huge role ... And social environment plays a huge role in-
Dr. Nemeroff: Well, remember that for major depression ... Not talking about bipolar disorder, but for major depression, about 35 to 40% of the risk for the disease is genetic. That means 60 to 65% is environmental, and I think a lot of this has to do with attachment. I think early life trauma disrupts attachment, and I think subsequent life stressors disrupt attachment, and if you follow these kids who've had terrible early lives, it's a very rocky adolescence and adulthood indeed.
David Carreon: Is it possible that somebody who has had a difficult childhood would be able to overcome that and fully remit or fully…
Dr. Nemeroff: Yeah, so most of our studies in this area have focused on trying to uncover genetic risk factors, that interact in a gene environment way to increase or modulate the risk for depression or PTSD in adulthood. What we've discovered is that there are some critical genes, of which certain of the SNPs, the variants, unfortunately markedly increase your risk for depression if you've been exposed to early trauma, and then their counterparts which are resilience genes that prevent it.
So I believe many of our patients are probably patients who've just had pretty bad luck. They've pulled a bad hand. They have three, four, five or six of the vulnerability genes coupled with early life trauma that result in an increased risk for depression. What's really interesting is in our studies, in the absence of early life trauma, these genetic variants have no impact on whether you get depressed or not. It's only in the face of early life trauma. It's sort of like ... Imagine the guy who has the risk gene for lung cancer but never smokes, right? No effect, right? But smokes three packs a day and 80% likelihood. That's what Caspi saw with the serotonin transporter gene. It's we've seen with the CRH and the FKBP5 gene. I don't want to bore you with the nomenclature, but there are gonna be a category of genes.
Now there is some data that both epigenetics is important, so the notion that life events change gene expression, not by changing the structure of the gene but by changing the expression of genes. That could be good or bad. It may be, if I was a betting person and I was Jessi's age, what I would do is I would like to look at the epigenetic consequences of psychotherapy. 'Cause I suspect, in my view, psychotherapy is a biological treatment, and I think it probably changes gene expression.
David Carreon: That would be a fascinating thing to circle back on in a few years. I imagine people are already doing work like that. That sounds ... Maybe the inverse of what you're saying about the epigenetics of child abuse, that at least we tell ourselves in psychotherapy that we're filling this role or that this relationship is analogous to the nurturing relationships of childhood.
Dr. Nemeroff: Well, it's absolutely essential, you know? I think we must be clear that genetics is not necessarily destiny. That genetics can be overcome, and gene expression can be modulated. There was a very nice study done in Seattle some years ago that I wrote a commentary for in the American Journal, which looked at two different foster care systems. One was funded by a foundation and was very high-end and hired the very best case workers, and every student in that program was guaranteed a full four-year college education if they completed it. That outcome was compared with a sort of standard foster care system in the public sector.
Obviously, and I'm not casting any aspersions on the public sector, but the fact is when resources were put into place to guarantee a selection of case workers, foster care parents who were rigorously screened for the best of intentions, the outcomes were better. So I think attachment really does matter, and you can't overcome adversity and genetics.
Jessi Gold: It begs the question whether social support or psychotherapy is somehow activating the resilience pathway or resilience genes in some other epigenetic way.
Dr. Nemeroff: You know, it's interesting having been brought up academically in the psychoanalytic era, and then seeing the pendulum swing. Every study of efficacy of psychotherapy has always had the same conclusion, which is it's the quality of the relationship between the psychotherapist and the patient that is the best predictor of outcome, regardless of whether you're using cognitive behavior therapy, interpersonal psychotherapy or psychodynamic psychotherapy. In my mind, that's exactly what it's about. It's about the attachment. It's learning how to trust people, it's having somebody help guide you in a certain way and a safe environment when you haven't experienced that. There's no chance on Earth it doesn't have an effect on your stress system, on your endocrine response to stress, and on inflammation.
David Carreon: I think that's a very optimistic note to shift into our last phase of questions here. We do rapid fire questions for our guests. So if the next two questions you could answer in one or two sentences. What's an area that psychiatry's going wrong, or an area that psychiatry can improve in?
Dr. Nemeroff: So our treatments just simply aren't as good as we would like them to be, and we have to be upfront and honest about it. If only 28% of patients are in remission after monotherapy with an SSRI, we have a problem, and we must teach practitioners and the community to be aggressive about treating depression with whatever it takes. RTMS, psychotherapy, ECT, any of the FDA-approved treatments. We haven't been good at that. That's one.
The second really quick answer has to do with the fact that we don't have parity. It's just simply a societal disgrace that our patients cannot get adequate treatment, and the notion that parity laws have passed and President Obama signed them ... The bottom line is my faculty get paid through third-party payers, minuscule amounts for their time compared to say oncologists or ophthalmologists or neurosurgeons. I have nothing against my colleagues in other branches of medicine, but if our patients can't get their treatment, and we can't pay our faculty, and practitioners can't get paid in the community, and companies are constantly denying medications we prescribe because everybody wants us to use generic medications, how can our patients get well?
Jessi Gold: Yeah. Just for people listening, before I ask you the next question, what would be the price difference for, let's say, going to a psychiatrist and getting reimbursed versus even just going to primary care or something?
Dr. Nemeroff: Well primary care's not a good example 'cause they don't get paid very well. Psychiatrists, pediatricians, general internists, family docs are paid very poorly. But depending on the plan and the state, Medicaid pays very poorly. As much of a help Obamacare was for many states, there was no provision for illegal immigrants to be paid. So many of us, particularly us in Miami but also in California, ended up seeing a lot of patients who were coming to the emergency room extremely sick, and there was no opportunity for them to be reimbursed at all. It's our job to take care of everybody, and so it's a pretty serious problem.
Jessi Gold: Yeah. The next question is, what's your favorite book? ...
Dr. Nemeroff: ... So I highly recommend ... One of my best friends is a novelist named John Katzenbach, whose father was Nicholas Katzenbach, the Attorney General of the United States. He writes really great psychiatric, psychological thrillers, and really delves into the minds of the characters. So I would highly recommend him. I would be remiss if I didn't mention that the fifth edition of our textbook of psychopharmacology was just released here at the APA.
But yeah, I tend to enjoy fiction very much. I just read a fabulous novel by a guy named Peter Heller called Celine. It's about a 62-year-old woman who's a private detective. Very cool.
Jessi Gold: Cool.
David Carreon: What advice would you give to a young doctor?
Dr. Nemeroff: So this is the golden age of psychiatry. All of the advances in neuroscience, molecular biology and genetics are now being applied, and in the next 10 years there's gonna be a sea change in terms of treatment. We're gonna develop personalized medicine in psychiatry. You're gonna see a patient, you're gonna get their genetics, you're gonna probably get imaging on them, you're gonna get inflammatory markers and based on those results, you'll be able to optimally match them to the best treatment and not have to play trial and error. That's gonna be a whole new world for us.
Jessi Gold: A lot less dart-playing.
Dr. Nemeroff: Alright.
Jessi Gold: Yeah. And the nice question is, who is a person, fiction or history, that you consider a hero?
Dr. Nemeroff: So ... Boy, that's a great question. I'd have to say Hank Aaron. I was in Atlanta for many years and Hank Aaron had the most incredible grace under pressure, at the toughest time. Here was somebody who broke Babe Ruth's record in baseball. The salary was never what the salaries are today, but he held his head high in the face of racial slurs in the most difficult time, particularly living in the South wasn't easy. I just respect the heck out of him.
David Carreon: I guess this is also related to another person, who's somebody who is, in history or the story of someone who had a depression and was able to push through?
Dr. Nemeroff: So there have been many folks in Hollywood that have suffered with depression. Some have been upfront about it, others have not. Certainly historically, we know Vincent van Gogh suffered with terrible depressions. ... Clearly Lincoln suffered with depression.
Probably the best example was Churchill. The black dog of depression, he's the one who named it, and went through just periods of melancholia that were just so severe. His biographer actually said that to liken his depressions to sadness was actually the same as likening a canker sore to a carcinoma. That's how severe he viewed his depressions.
David Carreon: Wow. Thank you for joining us on the show today. We really appreciate your time.
Jessi Gold: Yeah, thank you.
Dr. Nemeroff: It's my pleasure. Thank you.